Afflicting one out of 9 men over age 65, prostate cancer (PCA) is a leading cause of male cancer-related death, second only to lung cancer. The American Cancer Society estimates that 198,100 American men will be diagnosed with PCA and 31,500 will die this year .While effective surgical and radiation treatments exist for clinically localized PCA, metastatic PCA remains essentially, incurable and most men diagnosed with metastatic disease will succumb over a period of months to years. The molecular differences between metastatic prostate cancer and localized prostate cancer are not well established. Before prognostic markers and rational therapies can be developed to target this lethal form of prostate cancer, the molecular alterations associated with it need to be unmasked. Our overall hypothesis is that metastatic (advanced) prostate cancer expresses genes that can be used to predict the aggressive potential of clinically localized prostate cancer. These "signature" lethal genes have potential as prognostic biomarkers, therapeutic targets, and may play a role in the progression from localized disease. The advent of high-throughput genomic and proteomic techniques raises new hopes for identifying novel molecular targets for therapy. In this proposal, we will implement novel bioinformatic approaches to identify candidate lethal biomarkers from the gene expression profiles of metastatic prostate cancer (Aim 1 ). These lethal genes will be evaluated on clinically stratified prostate cancer tissue microarrays (Aim 2). The most promising candidates will be tested in a cohort of prostate needle biopsies for their ability to predict clinical aggressiveness (Aim 3). By pursuing these studies we hope to identify a set of lethal biomarkers that will be useful for guiding treatment decisions for individual patients and that may also have potential as therapeutic targets.